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Engineered bacteria detect spatial profiles in glucose concentration within solid tumor cell masses
Jan T Panteli1, Neil S Forbes2
1Department of Chemical Engineering, University of Massachusetts, 686 North Pleasant Street, Amherst, Massachusetts, 01003.
Abstract:
Tumor heterogeneity makes cancer difficult to treat. Many small molecule cancer drugs target rapidly dividing cells on the periphery of tumors but have difficulty in penetrating deep into tumors and are ineffective at treating entire tumors. Targeting both rapidly dividing and slower growing regions of tumors is essential to effectively treat cancer. A cancer drug carrier that penetrates deep into tumors and identifies metabolically activity could supply treatment to those areas based on the local microenvironment. We hypothesized that glucose sensing bacteria could identify sugar gradients in solid tumors. To test this hypothesis, a genetic circuit was designed to trigger expression of a green fluorescent protein (GFP) reporter through the chemotaxis-osmoporin fusion protein, Trz1, a receptor for sensing glucose and ribose sugars. E. coli equipped with the Trz1-GFP expression system, were administered to an in vitro model of a continuously perfused tumor tissue that mimics systemic delivery and clearance of bacteria through a blood vessel adjacent to a solid tumor. The level of GFP expressed, per bacterium, was time independent and indicated the glucose concentration as a function of penetration depth within the microfluidic tumors. The measured glucose concentration, correlated (P-value = 2.6 × 10(-5) ) with tumor cell viability as a function of depth. Mathematical analysis predicted drug delivery by glucose-sensing bacteria would eliminate a higher percentage of the viable tumor cell population than a systemically administered drug. Glucose-sensing bacteria could deliver cancer therapies with increased drug penetration and nutrient-dependent dosing to continuously treat viable regions of cancer tissue that have a higher prevalence for metastatic dissemination. Biotechnol. Bioeng. 2016;113: 2474-2484. © 2016 Wiley Periodicals, Inc.
Insights
Engineered bacteria sense glucose gradients in tumors, enabling targeted drug delivery. This approach promises improved cancer treatment by reaching deeper tumor regions and adapting dosage to metabolic activity.
Area of Science:
- Biotechnology
- Cancer Research
- Microbiology
Background:
- Tumor heterogeneity complicates cancer treatment.
- Conventional drugs struggle to penetrate deep into tumors.
- Targeting both fast-growing and slow-growing tumor regions is crucial.
Purpose of the Study:
- To engineer glucose-sensing bacteria for targeted cancer therapy.
- To investigate bacteria's ability to detect glucose gradients within tumors.
- To evaluate bacteria as a drug delivery system for improved tumor penetration and nutrient-dependent dosing.
Main Methods:
- Designed a genetic circuit in E. coli using Trz1-GFP to sense glucose and ribose.
- Utilized a microfluidic tumor model simulating systemic delivery and clearance.
- Measured GFP expression to indicate glucose concentration at different depths.
Main Results:
- GFP expression correlated with glucose concentration and tumor cell viability.
- Glucose concentration decreased with penetration depth.
- Mathematical models predicted superior tumor cell elimination by glucose-sensing bacteria compared to conventional drugs.
Conclusions:
- Glucose-sensing bacteria can identify and target metabolically active regions within tumors.
- This engineered bacteria system offers enhanced drug penetration and nutrient-dependent dosing.
- The approach holds potential for treating viable tumor regions prone to metastasis.
